Technical Field
The compositions and methods of the invention relate generally to detection of biomarkers for the diagnosis, prognosis, and monitoring of cancer. In particular, the invention relates to compositions and methods for detection of B-cell maturation antigen for the diagnosis, prognosis, and monitoring of multiple myeloma.
Description of the Related Art
Tumor necrosis factor receptor superfamily, member 17 (TNFRSF17, also designated as B-cell maturation antigen (BCMA) or CD269) is a receptor that was first identified in a T-cell tumor line (Laabi et al., 1992) and subsequently shown to be expressed in B lymphocytes as they mature (Laabi et al., 1994). BCMA ligands include BAFF (B cell-activating factor; TNFSF13B) and APRIL (a proliferation-inducing ligand; TNFSF13) (Rennert et al., 2000; Thompson et al., 2000). In multiple myeloma (MM) cell lines, these ligands activate cell proliferation pathways and upregulate anti-apoptotic proteins (Moreaux et al., 2004). Both ligands also bind the receptor TACI (transmembrane activator and CAML interactor; TNFRSF13B) (Gross et al., 2000; Wu et al., 2000; Yu et al., 2000). Additionally, BAFF binds to a third receptor, called BAFF-receptor (BAFFR; TNFRSF13C), whereas APRIL does not (Thompson et al., 2001; Day et al., 2005). The ligands BAFF and APRIL are members of the tumor necrosis family (TNF) and binding of TNF members to their receptors can lead to apoptosis, differentiation or proliferation (Smith et al., 1994). TNF family members act through autocrine, paracrine and endocrine mechanisms (Smith et al., 1994).
Transgenic mice that overexpress BAFF or are TACI-deficient display symptoms of systemic lupus erythematosus (SLE) and show B cell hyperplasia and increased levels of serum immunoglobulin (Ig) (McKay et al., 1999; Yan et al., 2001; Groom et al., 2002; Seshasayee et al., 2003). APRIL-deficient mice do not show B- or T-cell abnormalities (Varfolomeev et al, 2004). BCMA-deficient mice have normal peripheral B lymphocyte development, and their immune responses remain intact (Xu & Lam, 2001).
Serum BAFF levels are reported to be elevated in patients with autoimmune diseases and lymphoma (Cheema et al., 2001; Zhang et al., 2001; Oki et al., 2005). BCMA has been shown to be located intracellularly in plasma cell lines (Laabi et al., 1992, 1994). Surface expression of BCMA was found on human tonsilar B-cells (Thompson et al., 2000), and on human CD138-expressing MM cells (Novak et al., 2004). Malignant cells from Hodgkin lymphoma and Waldenstrom macroglobulinemia (WM) patients also express this protein (Elsawa et al., 2006; Chiu et al., 2007). However, serum levels of BCMA have not been previously reported in any disease.
Non-Hodgkin lymphoma (NHL) is a type of blood cancer that develops in the lymphatic system. The Leukemia and Lymphoma Society estimates that in 2011, about 502,943 people were living with NHL or are in remission (no sign of the disease). Like many other cancers, the incidence of NHL increases with age. The National Cancer Institute estimates that about 70,000 new cases will be diagnosed in 2012. Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults. Children don't get CLL. The incidence of CLL increases significantly among people aged 50 years and older. A small number of adults are diagnosed in their 30s and 40s. The Leukemia and Lymphoma Society estimates that about 105,000 people were living with (or in remission from) CLL and about 14,500 people in the United States were diagnosed with CLL in 2011.
Multiple myeloma is also a prevalent blood cancer, representing approximately 1% of all cancers and 2% of all cancer deaths. Although the peak age of onset of multiple myeloma is 65 to 70 years of age, recent statistics indicate both increasing incidence and earlier age of onset. Approximately 100,000 Americans currently have myeloma, and the American Cancer Society estimates that approximately 22,000 new cases of myeloma are diagnosed each year in the United States.
B-cell maturation antigen is expressed on the surface of normal and malignant B-cells (Laabi et al., 1992, 1994; Thompson et al., 2000; Novak et al., 2004). Most cell surface markers used to diagnose MM, CLL, and NHL are not elevated or reliably expressed in a large segment of the relevant patient populations. For example, one surface receptor present on normal and malignant B-cells, the interleukin (IL)-6 receptor, has been shown to be elevated in the serum of MM patients (Jones et al., 2001) but only in approximately 15% of patients (Stephens et al., 2012). Some serum markers of CLL including β2 microglobulin (Simonsson B et al., 1980), thymidine kinase (TK) (Kallander C F R et al., 1984), lactate dehydrogenase (LDH), (Lee J et al., 1987) soluble CD23 (Sarfati M et al., 1988), soluble CD27 (Van Oer's M H J et al., 1993) and ICAM-I (Christiansen I et al., 1994) have reported to be positively correlated to clinical stage, but need to be further evaluated. A study was undertaken to assess the clinical significance of the serum molecules in NHL. The results showed CD23, CD27, CD30, or CXCL13 were at 2.8- to 5.5-fold increased risk in B—NHL and VEGF, and bFGF was found to be an important prognostic factor in B—NHL (Benboubker L et al 2000). Elevated levels of IL-10, TNF-α and sTNF—R1 sTNF—R2 were significantly associated with increased risk of NHL. (Purdue M. P. et al 2011). However, those molecules are not NHL specific diagnosis or prognosis markers.
Due to the difficulty in assessing the location of bone marrow (BM)-based malignancies and the heterogeneous involvement of malignant cells within different BM sites, measurement of MM, CLL, and NHL tumor mass is indirect; and, thus, response to therapy is often difficult to determine. Besides blood and urine monoclonal Ig levels, existing blood markers used to determine MM tumor mass include: hemoglobin, urea nitrogen, calcium, albumin, creatinine, monoclonal protein, beta-2 microglobulin (β2M), IL-6, C-reactive protein, soluble IL-6 receptor, lactate dehydrogenase, thymidine kinase, and al-antitrypsin (Kyle, 1994). However, these markers are not produced directly by MM cells and thus, are not reliable. In addition, existing markers are even less useful for monitoring the response of patients to treatment, probably due to their widespread presence in many other not malignant cell types (Jones et al., 2001). Thus, existing markers have not proven to be reliable diagnostics or predictors of response to anti-cancer treatments for MM, CLL and NHL (Kyle, 1994).
Accordingly, the art is deficient in reliable diagnostic, prognostic, and treatment monitoring biomarkers of multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin's lymphomas. In addition, existing biomarkers do not correlate well with response to anti-cancer treatment, or with the extent or severity of the disease.